Research Article
Li Y, Zheng S, Long L, Jenn
Abstract
The cell type that normally limits the inflammatory and atherosclerotic process is the vascular Endothelial Cell (EC) that can be regulated by pro-inflammatory and various stresses. Toll-like Receptor-4 (TLR4) plays an important role in the pathogenesis of atherosclerosis, in part, by activating Apoptosis Signal-regulating Kinase 1 (ASK1) to initiate the activation of MAP kinases pathways and the expression of inflammatory genes. In the present study, we test the hypothesis that AGI-1067 acts as an anti-inflammatory agent by inhibiting the activation of ASK1 in human EC. Pretreatment of human aortic endothelial cells with AGI-1067 inhibits TLR4 ligand (LPS)-induced activation of ASK1 and the downstream p38 and c-Jun N-terminal Kinase (JNK) MAP kinases. LPS dissociate two endogenous inhibitors Thioredoxin-1 (Trx1) and 14-3-3 from ASK1, leading to ASK1 autoactivation. Interestingly, AGI-1067 inhibits the dissociation of Trx1, but not 14-3-3, from ASK1. However, inhibition of Trx1 dissociation from ASK1 by AGI-1067 is sufficient to suppress LPS-mediated phosphorylation of the transcription factors c-Jun and activating transcription factor 2, and inhibit LPS-induced inflammatory genes including vascular cell adhesion molecule 1, E-selectin, IL-6 and monocyte chemo attractant protein 1. Our findings suggest that AGI-1067 as a unique ASK1 inhibitor to inhibit TLR4- mediated ASK1 activation, contributing to its anti-inflammatory properties.